This is an autosomal dominant hamartomatous disorder with an incidence of approximately 1 per 12,000 live births. New mutations account for 70 % of cases, and the mutation rate is 2.5 × 10–5/haploid genome. Most serious morbidity is caused by the CNS lesions, which produce mental retardation and epilepsy, but renal angiomyolipomas can occasionally be life threatening, and RCC may occur at an increased rate, albeit infrequently (Washecka and Hanna 1991). Tuberous sclerosis is a multisystem disorder and the clinical features are diverse (Lendvay and Marshall 2003): Skin: Hypopigmented oval or “ash leaf” patches (80–90 %), facial angiofibromas (adenoma sebaceum, 40–90 %), Shagreen patches (20–40 %), forehead fibrous plaque (25 %), periungual fibromas (Koenen Tumours) (15– 50 %), and molluscum fibrosum pendulum (23 %).
Eyes: Hamartomas of the retina or optic nerve occur in about 50 % of patients with tuberous sclerosis. Just under half of these are calcified. Most retinal lesions do not grow, and although visual impairment from retinal or optic nerve astrocytoma is recorded, it is a rare complication (Robertson 1988).
CNS: Epilepsy (approximately 80 % of patients), mental retardation (50 %), and giant cell astrocytomas (5–10 %) are important features. Although MRI scanning demonstrates cortical tubers more easily than CT scanning, the latter is more sensitive in detecting small areas of intracranial calcification.
Intracranial Tumours are usually benign astrocytomas (subependymal nodules), which often calcify and are typically situated around the lateral aspects of the lateral ventricles. Infrequently, malignant giant cell astrocytomas develop from these subependymal nodules, most commonly near the foramen of Monro and resulting in bilateral (but often asymmetric) obstructive hydrocephalus. Less often, the Tumours occurs at the frontal or temporal horns of the lateral ventricle or in the third ventricle. On CT scan, giant cell astrocytomas have a mixed pattern with foci of calcification and areas of vascularity showing enhancement with intravenous contrast. Most Tumours are slow growing and distant metastases have not been reported. Subependymal giant cell astrocytomas can be demonstrated in about 8 % of patients, and although the proportion of tuberous sclerosis patients who develop intracranial hypertension is not accurately defined, it is estimated to be less than 3 % (Gomez 1988).
Teeth: Enamel “pits” due to enamel hypoplasia (70 %); however, these are very common in the general population and are not of any diagnostic value.
Kidney: Renal lesions occur in up to 75 % of cases and are a major cause of morbidity and mortality in older patients, and their importance has increased with the advent of more effective seizure control. The most frequent renal complications of tuberous sclerosis are angiomyolipomas (49 %) and renal cysts (32 %) (Cook et al. 1996). Angiomyolipomas are frequently multiple and bilateral. Most patients with a single angiomyolipoma do not have tuberous sclerosis, and patients with non- tuberous sclerosis-associated angiomyolipomas are usually middle-aged or elderly women (Robbins and Bernstein 1988). Angiomyolipomas in tuberous sclerosis patients present earlier (mean 32 versus 54 years) in non-tuberous sclerosis cases (Steiner et al. 1993). Most angiomyolipomas are asymptomatic, and although severe hemorrhage may occur, there is no indication to treat asymptomatic Tumours. There is no convincing evidence for malignant transformation occurring in an angiomyolipoma (Robbins and Bernstein 1988). Angiomyolipomas consist of disorganized smooth muscle cells, adipose tissue, and aberrant blood vessels, which do not have an internal elastic lamina and are prone to rupture. Larger Tumours tend to be symptomatic, and whereas small asymptomatic lesions may be kept under surveillance, it has been 1 that symptomatic angiomyolipomas ≥4 cm are investigated (angiography) and treated (embolization or renal sparing surgery). Renal cystic disease is the second most common renal manifestation, and renal cysts tend to occur at a younger age than angiomyolipomas. Severe renal cystic disease may result from a contiguous deletion of the TSC2 and PKD1 (autosomal dominant adult-onset polycystic kidney disease) genes (Brook-Carter et al. 1994; Sampson et al. 1997).
The risk of RCC in tuberous sclerosis is controversial (Tello et al. 1998), but although it appears to affect only a minority of cases (2 %), those cases reported were frequently bilateral (43 %), with an early age at onset (median 28 years) (Washecka and Hanna 1991).
GI: Benign, small, adenomatous rectal polyps.
Bones: Cysts (60 %), areas of periosteal new bone/sclerosis (60 %).
However, these findings are of no diagnostic value.
Cardiac: Rhabdomyomas are present in most infants with tuberous sclerosis. Thereafter many regress and echocardiographically demonstrable lesions occur in only about 30 % of adult patients. Obstructive symptoms or rhabdomyoma-induced arrhythmias are rare, and the likelihood of spontaneous regression favors conservative management in most cases.
Lungs: A specific feature of tuberous sclerosis is lymphangioleiomyomatosis (LAM) caused by an overgrowth of atypical smooth muscle cells. It is nearly always restricted to women and is very rare in the general population (1 per million) (Johnson and Tattersfield 2002) Honeycomb fibrosis also seen but is rare.
Conventional diagnostic criteria for tuberous sclerosis are shown in Table 1. The manifestations of tuberous sclerosis can be mild and easily overlooked so that the assessment of at-risk relatives must be performed assiduously. In addition to careful examination of the skin (including Wood’s lamp examination) and nails, further examinations usually indicated include brain CT or MRI scans, renal ultrasound, specialist eye examination, and echocardiogram (in children). Dental pits are more common in patients with tuberous sclerosis, but their usefulness as a diagnostic feature is limited because many normal persons have small numbers of these. Truly non-penetrant gene carriers are extremely unusual so that the risk to individuals with negative investigations as outlined above will be small. A frequent diagnostic problem occurs in assessing the significance of a single ambiguous lesion (e.g., ash leaf patch or equivocal CT scan finding) in an at-risk individual. Parents of a child with tuberous sclerosis who have been fully investigated with negative results should be given a 2 % recurrence risk for tuberous sclerosis in further children, because of the possibility of germline mosaicism or non-penetrance.
Table 1 Diagnostic criteria for tuberous sclerosis. A diagnosis of tuberous sclerosis is suggested if a single primary or two secondary diagnostic features are present
|Primary features||Secondary features|
|Classical shagreen patch||Ash leaf patch (hypomelanotic macules)|
|Ungual fibroma||Gingival fibroma|
|Retinal hamartoma||Bilateral polycystic kidney|
|Facial angiofibromas||Cardiac rhabdomyoma|
|Subependymal glial nodule||Cortical tuber Radiographic “honeycomb” lungs|
|(on CT scan)|
|Renal angiomyolipoma||Infantile spasms|
|Lymphangioleiomyomatosis (lung)||Myoclonic, tonic, or atonic seizures First-degree relative with tuberous sclerosis Forehead fibrous plaque Giant cell astrocytoma|
After Gomez (1988)
The presence of locus heterogeneity in tuberous sclerosis is firmly established, with two genes (TSC1 and TSC2, respectively) mapped at 9q34 and 16p13.3 adjacent to the autosomal dominant polycystic kidney locus (APKD1). The TSC2 gene was isolated first, and the TSC1 gene was cloned 10 years after the initial mapping to chromosome 9 (van Slegtenhorst et al. 1997). Loss of heterozygosity at TSC1 or TSC2 is observed in hamartomas from tuberous sclerosis patients, consistent with both genes having a Tumours suppressor function (Sepp et al. 1996). Half of familial cases are linked to TSC1 and half to TSC2, but 80 % of sporadic cases have TSC2 mutations (Jones et al. 1999). The proteins specified by the TSC1 and TSC2 genes (hamartin and tuberin, respectively) interact directly with, and mutations affecting either gene result in the tuberous sclerosis phenotype (Hodges et al. 2001). Hamartin or tuberin inactivation leads to dysregulation of the mammalian target of rapamycin (mTOR) and abnormal cell growth (Inoki et al. 2005). This finding suggests that inhibitors of mTOR (e.g., rapamycin) have a potential role in tuberous sclerosis therapy.
Large kindreds with tuberous sclerosis are unusual, and in most cases reliable presymptomatic or prenatal diagnosis using linked DNA markers is not usually feasible. Molecular diagnosis by direct mutation analysis is possible, but the TSC2 gene is very large and mutations are heterogeneous and so molecular diagnosis may not be available. All parents of apparently isolated cases of tuberous sclerosis should undergo detailed clinical examination (including examination of nails and Wood’s light), a CT or MRI brain scan, and renal and liver ultrasound examination. If these investigations are negative, the recurrence risk is reduced to approximately 2 %.
The clinical features of germline mutations in TSC1 and TSC2 appear similar, except that the presence of severe renal cystic disease is strongly correlated with deletions of both TSC2 and APKD1 genes (Brook-Carter et al. 1994), and intellectual disability is more frequent in sporadic cases, which are mostly caused by TSC2 mutations. Renal carcinoma has been described in families linked to TSC1 and to TSC2, and although RCC is uncommon in
tuberous sclerosis, a germline mutation in rat TSC2 gene is responsible for the Eker rat model of hereditary renal carcinoma (Kobayashi et al. 1995).
The investigation of asymptomatic at-risk relatives has been described. For unequivocally affected individuals, management is directed towards the active clinical problems; however, regular surveillance of asymptomatic angiomyolipomas may be undertaken, particularly if large (>4 cm).
Symptomatic angiomyolipomas may be investigated by angiography and, particularly if larger than 4 cm. Diameter, embolization or renal sparing surgery performed.